Background: Methylmalonic acidemia (MMA) is an inborn error in the catabolism of branched-chain amino acids and is caused by mutations in the methylmalonyl-CoA mutase (MUT) gene. The MUT enzyme is located in the mitochondrial inner space and has a requirement for 5-deoxyadenosylcobalamin. Although MUT is expressed in many tissues, including the liver, brain and kidney, the patients experience organ specific disease such as basal ganglia dysfunction, pancreatitis and chronic kidney disease. As survival in MMA has increased, renal disease has become very important. Animal models have suggested that mitochondrial dysfunction with megamitochondria formation in selected cell types might contribute to specific disease manifestations but the lack of supporting studies has hampered efforts to discern the pathological features of MMA.Design: Here we describe light and ultrastructural studies on the native kidney and liver from a 19 year-old patient with vitamin B12 non-responsive MMA, who underwent a combined transplant. She presented as a newborn with coma, metabolic ketoacidosis and massive hyperammonemia; severe MUT deficiency was identified. Stable in the first decade of life, she later developed progressive renal dysfunction.Results: Kidney sections showed proximal tubular megamitochondria (proximal tubule vacuoles by light microscopy). In electron microscopy studies, the most dramatic changes were restricted to proximal tubules with all mitochondrial profiles shifted to large circular shapes with diminished cristae. There was loss of the plasma membranes of the lateral cellular interdigitations, but the brush border was maintained in many tubules. Measurements of mitochondrial size showed a marked increase of individual mitochondrial area from 0.38 ± 0.036 to 1.71 ± 0.78 µM2 (SE ±; p<0.0001). There was marked interstitial fibrosis and tubular atrophy involving the subcapsular zone, medullary rays and the labyrinth. The liver pathology of mitochondrial enlargement (the basic abnormality in this patient) in MMA has been reported in mouse models and in a single human case, while the detailed renal pathology has not been described in humans.Conclusions: With this study, we provide evidence that the renal mitochondropathy of MMA is characterized by megamitochondria formation in the proximal tubules of the kidney. Such changes may lead to tubulo-interstitial disease and have implications for treatments directed toward maximizing mitochondrial function in these patients.Category: Kidney (does not include tumors)